Based on the observation that the pyrrolo [2,3-d] pyrimidine nucleoside antibiotic sangivamycin, in its nucleoside form, is a potent inhibitor of protein kinase C (PKC), analogs of this antibiotic modified at the 5'-and at the 5-position are to be synthesized. Alterations at the 5'-position, including the introduction of fluoro, amino, carboxyl, carboxamide and sulfamoyl groups, are to be undertaken in order to prevent phosphorylation of the nucleosides for the purpose of preserving their target specificity and to increase their binding capacity. Changes at the 5-position, including replacement of the carboxamide group with thiocarboxamide, carboxyl, carboxymethyl or nitromethyl are to be introduced in order to increase the binding capacity of the agents to PKC. The synthetic effort is to be guided by evaluating the effect the newly prepared analogs exert on purified PKC, on camp-dependent protein kinase and on the growth of various tumor cell lines in vitro. Significantly potent PKC inhibitors are to be used for studies on the role PKC plays in initiating and maintaining tumor cell growth. These studies will include determinations on the effect od the agents on growth-factor binding, on growth factor- mediated increases in intracellular Ca2+ and inositol phosphate levels, and on the level and intracellular localization of PKC. Where indicated, the metabolic disposition of the agents in the target cells is also to be assessed. Since PKC is considered to play an important role in the transmittal of external signals to the cell's interior, these studies are expected to provide information not only on the potential utility of PKC as a target for therapeutic exploitation, but also on the contribution PKC makes to the maintenance of tumor cell growth.